2-methoxyimino-2 (pyrinyloxymethyl) phenyl acetamides with polyether derivatives on the pyridine ring

ABSTRACT

The present invention provides novel 2-methoxyimino-2-(pyridinyloxymethyl) phenyl acetamide compounds with polyether substituents on the pyridine ring, their use as fungicidal compounds, and their use in fungicidal compositions comprising at least one of the 2-methoxyimino-2-(pyridinyloxymethyl)phenyl acetamide compounds as the active ingredient.

PRIORITY CLAIM

This application claims a priority based on provisional application No.60/100,493 which was filed in the U.S. Patent and Trademark Office onSep. 16, 1998.

BACKGROUND OF THE INVENTION

The present invention provides novel2-methoxyimino-2-(pyridinyloxymethyl)phenyl acetamide compounds withpolyether substituents on the pyridine ring, their use as fungicidalcompounds, and their use in fungicidal compositions comprising at leastone of the 2-methoxyimino-2-(pyridinyloxymethyl)phenyl acetamidecompounds as the active ingredient.

SUMMARY OF THE INVENTION

This invention provides novel2-methoxyimino-2-(pyridinyloxymethyl)phenyl acetamide compounds offormula (1), below

wherein

m is an integer 0-3;

L is —O—, —CH₂—, —SO_(n)—, -CH₂O—, —OCH₂—, —CH₂S—, —SCH₂—, —CH═CH—,—C≡C—, or

wherein n is an integer 0-2;

X, Y, and Z are each independently H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆ alkoxy, halo, nitro, carbo-C₁₋₆ alkoxy, cyano, C₁₋₆alkylthio, or halo-C₁₋₆ alkylthio;

W is H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, halo-C₁₋₄ alkyl, or C₁₋₄alkylthio;

A is O, S, NR³, OCH₂, SCH₂;

B is O or S;

R¹ is a C₁-C₄ alkyl group (optionally substituted by alkenyl,cycloalkyl, alkoxy, alkoxycarbonyl, arylalkyl, cyano, cyanoalkyl, halo,or haloalkyl), optionally substituted phenyl, or an optionallysubstituted aryl or heteroaryl ring;

R² is a C₁-C₈ alkyl, (optionally substituted by alkenyl, cycloalkyl,alkoxy, alkoxycarbonyl, arylalkyl, cyano, cyanoalkyl, halo, orhaloalkyl), optionally substituted phenyl, or an optionally substitutedaryl or heteroaryl ring;

or the group R¹—B—R² can be an optionally substituted 4-6 memberedsaturated or unsaturated heterocyclic ring;

or the group —A—R¹—B—R² can be an optionally substituted 4-6 memberedsaturated or unsaturated heterocyclic ring containing 2 or moreheteroatoms; and

R³ is H or C₁₋₆ alkyl.

The present invention also provides compositions comprising one or morecompounds of Formula (1) in combination with phytologically-acceptablecarriers and/or diluents. Methods for the use of compounds of formula(1) and compositions comprising one or more compounds of formula (1) arealso provided.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this document, all temperatures are given in degrees Celsiusand all percentages are weight percentages, unless otherwise stated.

The term “halogen” or “halo” refers to F, Cl, I, or Br.

The term “alkyl”, “alkenyl”, or “alkynyl” refers to a straight chain orbranched chain carbon radical containing the designated number of carbonatoms.

The term “alkoxy” refers to a straight or branched chain alkoxy group.

The term “halo alkyl” refers to a straight or branched alkyl groupsubstituted with one or more halo atoms. The term “halo alkoxy” refersto an alkoxy group substituted with one or more halo atoms.

The term “aryl” or “Ph” refers to a phenyl group. The term “substitutedaryl” refers to a phenyl group substituted with C₁-C₆ alkyl, C₁-C₆alkoxy, halo-C₁-C₆ alkyl, halo-C₁-C₆ alkoxy, halo, nitro, carbo-C₁-C₆alkoxy, or cyano. The term “heteroaryl” refers to pyridyl, pyridinyl,pyrazinyl, pyridazinyl or thiophene.

The term “Me” refers to a methyl group. The term “Et” refers to an ethylgroup. The term “Pr” refers to a propyl group. The term “Bu” refers to abutyl group. The term “EtOAc” refers to ethyl acetate.

The term “ppm” refers to parts per million. The term “psi” refers topounds per square inch.

The term “M.P.” refers to melting point. The term “bp” refers to boilingpoint.

While all the compounds of this invention have fungicidal activity,certain classes of compounds may be preferred for reasons such as, forexample, greater efficacy or ease of synthesis.

A preferred class includes those compounds of Formula (2), below

wherein the substituents are as defined in Formula (1), above.

A more preferred class includes those compounds of Formula (3), below

wherein L is either —O—, —CH₂O—, or —OCH₂—, and the other substituentsare as defined in Formula (1), above.

A next more preferred class includes those compounds of Formula (4),below

wherein the substituents are as defined in Formula (1), above.

A next more preferred class includes those compounds of Formula (5),below

wherein the substituents are as defined in Formula (1), above.

A next more preferred class includes those compounds of Formula (5-1),below

wherein the substituents are as defined in Formula (1), above.

EXAMPLES

Compounds of the present invention may be prepared by routes commonlyknown in the art using commercially available or readily synthesizedstarting materials. Such general procedures are described in Scheme 1and Scheme 2, below, wherein the substituents are as described informula (1), above, and V is a leaving group, such as, for example, F,Cl, or SO₂CH₃.

An compound of formula (7) is reacted with an appropriately substitutedpyridine derivative of formula (6) in the presence of a base in anaprotic solvent. Examples of an appropriate solvent for this reactionwould include, but are not restricted to, tetrahydrofuran, dimethylsulphoxide, acetone, acetonitrile, dimethyl formamide,N-methylpyrrolidinone. Examples of an appropriate base for this reactionwould include, but are not restricted to, sodium hydride, potassiumhydride, potassium t-butoxide, potassium carbonate, or a tertiary aminederivative such as triethylamine.

The intermediate so formed is then reacted with a compound of formula(9) in the presence of a base in an aprotic solvent. Examples of anappropriate solvent for this reaction would include, but are notrestricted to, tetrahydrofuran, dimethyl sulphoxide, acetone,acetonitrile, dimethyl formamide, N-methylpyrrolidinone. Examples of anappropriate base for this reaction would include, but are not restrictedto, sodium hydride, potassium hydride, potassium carbonate, potassiumt-butoxide, or a tertiary amine derivative such as triethylamine.

A compound of formula (9) is reacted with an appropriately substitutedpyridine derivative of formula (6) in the presence of a base in anaprotic solvent. Examples of an appropriate solvent for this reactionwould include, but are not restricted to, tetrahydrofuran, dimethylsulphoxide, acetone, acetonitrile, dimethyl formamide,N-methylpyrrolidinone. Examples of an appropriate base for this reactionwould include, but are not restricted to, sodium hydride, potassiumhydride, potassium carbonate, potassium t-butoxide, or a tertiary aminederivative such as triethylamine.

The intermediate so formed is then reacted with a compound of formula(7) in the presence of a base in an aprotic solvent. Examples of anappropriate solvent for this reaction would include, but are notrestricted to, tetrahydrofuran, dimethyl sulphoxide, acetone,acetonitrile, dimethyl formamide, N-methylpyrrolidinone. Examples of anappropriate base for this reaction would include, but are not restrictedto, sodium hydride, potassium hydride, potassium carbonate, potassiumt-butoxide, or a tertiary amine derivative such as triethylamine.

The following examples further illustrate this invention. The examplesshould not be construed as limiting the invention in any manner.

Example 1 2-Fluoro-6-(2.2-dimethyl-1,3-dioxolane-4-methoxy)pyridine

Potassium tert-butoxide (2.14 g, 19.1 mmol) was added to a solution of2,2-dimethyl-1,3-dioxolane-4-methanol (2.40 g, 18.2 mmol) in 50 mL THF.The resulting mixture was added slowly to a solution of2,6-difluoropyridine (2.08 g, 18.2 mmol) in THF (50 mL) which wasstirred while cooling in an ice bath. After returning the mixture slowlyto room temperature and stirring overnight, the mixture was quenchedwith brine and extracted with EtOAc. Combined extracts were dried withNa₂SO₄, then concentrated to dryness. Silica gel column chromatography(10-20% EtOAc in hexane) yielded2-fluoro-6-((2,2-dimethyl-1,3-dioxolanyl)-4-methoxy)pyridine (2.75 g,67%)as a clear oil.

Example 2 Benzeneacetamide,2-[[[6-((2,2-dimethyl-1,3-dioxolanyl)-4-methoxy)-2-pyridinyl]oxy]methy]-α-(methoxyimino)-N-methyl-

2-(Hydroxymethyl)-α-(methoxyimino)-N-methyl-benzeneacetamide (1.00 g,4.50 mmol) was dissolved in 10 mL THF, then treated slowly with NaH(0.36 g, 60% oil dispersion, 9.0 mmol) while cooling in an ice bath.Then, 2-fluoro-6-((2,2-dimethyl-1,3-dioxolanyl)-4-methoxy)pyridine (1.23g, 5.40 mmol) in 10 mL THF was added dropwise, and the bath was allowedto return to room temperature overnight. The mixture was stripped todryness in vacua, resuspended in 20 mL DMSO, and stirred at roomtemperature overnight, then it was heated to 50° C. for one hour,followed by stirring at room temperature overnight. Another portion ofNaH (0.36 g, 60% oil dispersion, 9.0 mmol) was added, and the mixturewas stirred at room temperature overnight. After workup as above withbrine and EtOAc, the concentrated extract was purified by silica gelcolumn chromatography (10-50% EtOAc in hexane) to yield the product(0.76 g, 39%) as an oil.

Example 3 Benzeneacetamide,2-[[[6-fluoro-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-

NaH (7.0 g, 60% oil dispersion, 0.176 mol) was added portionwise overfive minutes to a stirred slurry of2-(hydroxymethyl)-α-(methoxyimino)-N-methyl-benzeneacetamide (35.8 g,0.161 mol) in 700 mL THF. After the resulting mixture was stirred for3.25 hours, 2,6-difluoropyridine (15.4 g, 0.134 mol) was added neat overa 20 minute period, and the mixture was stirred overnight at roomtemperature. Water (250 mL) was added, THF was removed in vacuo, and theaqueous residue was extracted three times with 250 mL CH₂Cl₂. Thecombined extracts were washed with brine (250 mL), filtered throughNa₂SO₄, and concentrated in vacuo. The residue was purified by silicagel chromatography (5% CH₃CN in CH₂Cl₂) to yield 2-[[[6-fluoro-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-benzeneacetamide(33.2 g, 78%).

Example 4 Benzeneacetamide,2-[[[6-((2,2-dimethyl-1,3-dioxolanyl)-4-methoxy)-2-pyridinyl]oxy]methyl-α-(methoxyimino)-N-methyl-

Two portions of NaH (total 4.1 g, 60% oil dispersion, 0.102 mol) wereadded to a stirred solution of 2,2-dimethyl-1,3-dioxolane-4-methanol(13.3 g, 0.102 mol) in 400 mL THF. The mixture was stirred two hours atroom temperature, becoming gelatinous.2-[[[6-Fluoro-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-benzeneacetamide(27.0 g, 0.0851 mol) was added neat in one portion, then the resultingcloudy gold solution was stirred at room temperature one hour, heated to55° C. for 3 hours, and stirred at room temperature overnight. Water(250 mL) was added, the layers were separated, and THF was removed fromthe organic layer in vacuo. The residue was taken up in CH₂Cl₂, thenpartitioned against the original aqueous phase. The aqueous phase wasthen extracted four times with 125 mL CH₂Cl₂. All CH₂Cl₂ fractions werecombined, washed with brine (250 mL), filtered through Na₂SO₄, andconcentrated in vacuo to crude product. The crude product was purifiedthrough silica gel chromatography (3-8% CH₃CN in CH₂Cl₂) to yield theproduct (22.7 g, 60%) as an oil.

Example 5 2-Fluoro-6-(2-propoxyethoxy)pyridine

2-Propoxyethanol (1.89 g, 18.1 mmol) was dissolved in 50 mL THF, treatedwith potassium tert-butoxide (3.05 g, 27.2 mmol), stirred to uniformsolution, placed in an addition funnel, and added dropwise to a solutionof 2,6-difluoropyridine in 50 mL THF. After stirring overnight at roomtemperature, the solution was diluted with brine and extracted withether. The ether extracts were combined and dried over Na₂SO₄, thenconcentrated in vacuo to yield 2-fluoro-6-(2-propoxyethoxy)-pyridine(3.33 g, 93%) as a yellow oil.

Example 6 Benzeneacetamide,2-[[[6-(2-propoxyethoxy)-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-

2-(Hydroxymethyl)-α-(methoxyimino)-N-methyl-benzeneacetamide (1.11 g,5.00 mmol) was dissolved in 100 mL DMSO, then treated portionwise withNaH (0.40 g, 60% oil dispersion, 10 mmol) while stirring to a cloudysolution. 2-Fluoro-6-(2-propoxyethoxy)pyridine (1.20 g, 6.00 mmol) wasadded, and the mixture was stirred overnight at room temperature. Themixture was diluted with brine and extracted with EtOAc. The combinedEtOAc extracts were dried over Na₂SO₄ and concentrated in vacuo and theresidue was purified by silica gel chromatography (0-50% EtOAc inhexane) to yield the product (0.90 g, 43%) as an oil.

Example 7 Benzeneacetamide,2-[[[6-(2-propoxyethoxy)-2-Pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-

2-Propoxyethanol (12.5 g, 0.12 mol) was dissolved in 500 mL THF, treatedwith NaH (4.8 g, 60% oil dispersion, 0.12 mol) portionwise over 5minutes, and stirred at room temperature for two hours.2-[[[6-Fluoro-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-benzeneacetamide(31.7 g, 0.1 mol) was added portionwise over 10 minutes, then themixture was stirred at room temperature for one hour, heated to 55° C.for one hour, and stirred to room temperature overnight. The reactionwas quenched with 400 mL water, stripped of THF in vacuo, and extracted3 times with 300 mL CH₂Cl₂. The combined extracts were dried overNa₂SO₄, filtered, and concentrated in vacuo to yield an oil. Thisresidue was purified via silica gel chromatography (pentane:EtOAc, 2:1)to yield an oil which was dried in vacuo, then triturated with a smallamount of ether to yield the product (22.2 g, 55%) as a white powderafter drying. M.P. 53-540° C.

Example 8 Benzeneacetamide, 2-[[[6-(2-(2-ethoxyethoxy)ethoxy)-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-

2-(Hydroxymethyl)-α-(methoxyimino)-N-methyl-benzeneacetamide (0.62 g,2.8 mmol) in 10 mL THF was treated portionwise with NaH (0.22 g, 60% oildispersion, 5.6 mmol) while cooling in an ice bath.2-Fluoro-6-(2-(2-ethoxyethoxy)ethoxy)pyridine (1.00 g, 3.35 mmol) wasadded, and the mixture was allowed to return to room temperature. After3 hours, the mixture was diluted with brine, treated with sufficientdilute HCl to render it weakly acidic, and extracted with EtOAc. Thecombined EtOAc extracts were dried over Na₂SO₄, then concentrated invacuo. The residue was purified via silica gel chromatography (0-50wEtOAc in hexane) to yield the product (0.65 g, 54%) as an oil.

Example 9 Benzeneacetamide,2-[[[6-(2-(2-(1-methylethoxy)ethoxy)-2-Pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-

Sodium hydride (0.29 g, 60% oil dispersion, 7.2 mmol) was washed withhexane, then suspended in 20 mL DMF. 2-(1-Methylethoxy)ethanol (0.75 g,7.2 mmol), dissolved in 5 mL DMF, was added to the NaH suspension over 5minutes, then the mixture was stirred at room temperature for 40minutes. This mixture, with the aid of 20 mL additional DMF, was addedto a stirred solution of2-[[[6-fluoro-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-benzeneacetamide(2.28 g, 7.2 mmol) in 30 mL DMF. The reaction was stirred at roomtemperature one hour, then heated to 60° C. for 19 hours. Additional2-(1-methylethoxy)ethanol (2.50 g, 24.0 mmol) was dissolved in 30 mLDMF, treated with NaH (0.96 g, 60% oil dispersion), stirred for 5-10minutes, and transferred to the above reaction mixture. The new mixturewas heated to 60° C. for one hour, then diluted with 800 mL water. Theaqueous suspension was extracted twice with 100 mL ether, then twicewith 60 mL ether. The combined ether extracts were washed twice with 100mL water, diluted with 150 mL hexane, filtered through phase-separatingpaper, concentrated in vacuo, and concentrated twice more with 100 mLtoluene. The residue was purified over silica gel (step gradient: 4, 5,8, and 10% CH₃CN in CH₂Cl₂) to yield the product (1.04 g, 36%) as anoil.

Example 10 2,3-Dichloro-6-(2-ethoxyethoxy)pyridine &3,6-Dichloro-2-(2-ethoxyethoxy)pyridine

2,3,5-Trichloropyridine (9.12 g, 0.050 mol) and 2-ethoxyethanol (5.40 g,0.060 mol) were dissolved in 50 mL DMSO, followed by portionwiseaddition of NaH (2.4 g, 60% dispersion in oil, 0.060 mol). The mixturewas heated to 80° C. for 3 hours, stirred at room temperature overnight,then heated to 120° C. for 5 hours. The reaction mixture was thendiluted to 900 mL with brine, and extracted three times with 100 mLether. The ether extracts were combined, washed twice with 100 mL water,diluted with 300 mL hexane, filtered through phase-separating paper, andconcentrated in vacuo. The residue was purified via silica gelchromatography (first column with 10-50% EtOAc in hexane; second columnwith 0-10% EtOAc in hexane). Concentration of pure fractions gave3,6-dichloro-2-(2-ethoxyethyl)pyridine as the major isomer (5.78 g whitesolid, M.P. 33-34° C.) and 2,3-dichloro-6-(2-ethoxyethyl)pyridine as theminor isomer (1.43 g white solid, M.P. 47-480° C.).

Example 11 3-Chloro-2-(2-ethoxyethoxy)-6-(methylthio)pyridine

3,6-Dichloro-2-(2-ethoxyethyl)-pyridine (1.18 g, 5.00 mmol) wasdissolved in 25 mL DMSO, treated with NaSCH₃ (0.53 g, 7.5 mmol), andstirred at room temperature overnight. The mixture was diluted withbrine, then extracted with EtOAc. The combined EtOAc extracts werecombined, dried over Na₂SO₄, and concentrated in vacuo to yield3-chloro-2-(ethoxyethyl)-6-(methylthio)pyridine (0.91 g, 76%) as ayellow oil, used without further purification.

Example 12

3-Chloro-2-(2-ethoxyethoxy)-6- -(methylsulphonyl)pyridine

3-Chloro-2-(ethoxyethyl)-6-(methylthio)pyridine (0.91 g, 3.7 mmol) wasdissolved in 25 mL CH₂Cl₂, cooled in an ice bath, and was treated withm-chloroperoxybenzoic acid (MCPBA; 2.53 g of reagent estimated to be50-55% pure, ca. 7.3-8.0 mmol) added dropwise in 25 mL CH₂Cl₂. Thereaction was allowed to return to room temperature and stirredovernight. After dilution with more CH₂Cl₂, the mixture was washed withsaturated Na₂CO₃, then water, and was concentrated to yield3-chloro-2-(ethoxyethyl)-6-(methylsulphonyl)pyridine (0.60 g, 58%) as aclear oil, used without further purification.

Example 13 Benzeneacetamide,2-[[[5-chloro-6-(2-ethoxyethoxy)-2-pyridinyl]oxy]methyl]-α-(methoxyimino)-N-methyl-

2-(Hydroxymethyl)-(-(methoxyimino)-N-methyl-benzeneacetamide (0.60 g,2.1 mmol) was dissolved in 20 mL DMSO, treated portionwise with NaH(0.14 g, 60% oil dispersion, 3.6 mmol), and stirred.3-Chloro-2-(ethoxyethyl)-6-(methylsulphonyl)pyridine was dissolved in 25mL DMSO, then added dropwise to the above mixture. After stirring atroom temperature overnight, the reaction was quenched with brine andextracted with EtOAc. The EtOAc extracts were combined, dried overNa₂SO₄, and concentrated in vacuo. The residue was purified via silicagel chromatography (25-60% EtOAc in hexane) to yield the product (0.27g, 30%), M.P. 94-96° C.

The following tables identify various compounds of the illustratedgeneral formulas prepared analogous to the procedures illustrated in thepreceding examples:

Compound number W X Y Z A R¹—B—R² 1 H Cl H Cl OCH₂ 2,2-dimethyl-1,3-dioxolan-4-yl 2 H H H H OCH₂ 2,2-dimethyl-1,3- dioxolan-4-yl 3 H Cl H ClOCH₂ 2-furyl (E-isorner) 4 H Cl H Cl OCH₂ 2-furyl (Z-isomer) 5 H H H HOCH₂ 2-furyl 6 H H H H OCH₂ 2-methyl-2- trifluoromethyl-1,3-dioxolan-4-yl 7 H H H H OCH₂ 3-methyloxetan-3-yl 8 H H H H OCH₂ 2-furyl9 H H H H OCH₂ 2-tetrahydropyranyl 10 H H H H OCH₂ 2-tetrahydrofuranyl11 H H H H OCH₂ 2,2-di(trifluoromethyl)- 1,3-dioxolan-4-yl 12 H H H H S5-methylthio-1,3,4- thiadiazol-2-yl 13 H H H H S 7-ethoxybenzo-thiazol-2-yl 14 H H H H O 2-tetrahydropyranyl 15 H H H H S 2-thienyl

Compound Number W X Y Z A R¹ B R² 16 —H —Cl —H —Cl O —CH₂CH₂— OC₂H₅OC₂H₄— 17 —H —H —H —H O —CH₂CH₂— O C₂H₅— 18 —H —Cl —H —Cl O —CH₂CH₂—O C₂H₅— 19 —H —Cl —H —Cl O —CH₂CH₂— O C₃H₇OCH₂CH₂— 20 —H —Cl —H —Cl C—CH(OME)CH₂— O CH₃— 21 —H —H —H —H O —CH₂CH₂— O C₂H₅OC₂H₄— 22 —H —H —H—H O —CH(OME)CH₂— O CH₃— 23 —H —Cl —H —Cl NH —CH₂CH₂— O C₂H₅— 24 —H —H—H —Cl O —CH₂CH₂— O C₂H₅— 25 —H —H —H —H O —CH₂CH₂— O CH₃— 26 —H —Cl —H—Cl O —CH₂CH(CH₃)— O nC₃H₇— 28 —H —Cl —H —Cl O —CH₂CH(CH₃)— O CH₃— 29 —H—Cl —H —Cl O —CH₂CH₂— O nC₃H₇— 30 —H —H —H —H O —CH₂CH(CH₃)— O CH₃— 31—H —H —H —H O —CH₂CH₂— O nC₃H₇— 32 —H —H —H —H O —CH₂CH(CH₃)— O nC₃H₇—33 —H —Cl —H —Cl O —CH₂CH₂— O CH₃— 34 —H —H —H —H S

O CH₃— 35 —H —H —H —H S

O CH₃— 36 —H —H —H —H O —CH₂CH₂— O nC₃H₇— 38 —H —H —H —H O

O CH₃— 39 —H —H —H —H S

O CH₃— 40 —H —H —H —H S

O CH₃— 41 —H —H —H —H S

O CF₃— 42 —H —H —H —H S

O CH₃— 43 —H —H —H —H S

S CH₃— 44 —H —H —H —H S

O CF₃— 45 —H —H —H —H O —CH₂CH₂— S C₂H₅— 46 —H —H —H —H O —CH₂CH₂— OnC₄H₉— 47 —H —H —H —H O —CH₂CH₂— S nC₄H₉— 48 —H —H —H —H O —CH₂CH₂— SnC₄H₉— 49 —H —H —H —H O —CH₂CH₂— O Ph— 50 —H —H —H —H S —CH₂CH₂— S C₂H₅—51 —H —H —H —H O —CH₂CH₂— O PhCH₂— 52 —H —H —H —H S —CH₂CH₂— S tC₄H₉— 53—H —H —H —H O —CH₂CH₂— O iC₃H₇— 54 —H —H —H —H O —CH₂CH2CH₂— O iC₃H₇— 55—H —H —H —H O —CH₂CH2CH₂— O C₂H₅— 56 —H —H —H —H O —CH₂CH₂— O2-Ethylhexyl- 57 —H —H —H —H S

O CH₃— 58 —H —H —H —H O —CH₂CH₂— O Cyclobutyl- 59 —F —H —H —H O —CH₂CH₂—O nC₃H₇— 60 —Cl —H —H —H O —CH₂CH₂— O nC₃H₇— 61 —H —H —H —H O —CH₂CH₂— OnC₅H₁₁— 62 —H —H —H —H O —CH₂CH₂— O Cyclohexyl- 63 —Cl —H —H —H O—CH₂CH₂— O C₂H₅— 64 —H —H —H —H O

O C₂H₅— 65 —H —H —H —H O —(CH₂)₄— O C₂H₅— 66 —H —H —H —H O —(CH₂)₅— OPhCH₂— 67 —H —H —H —H O

O C₂H₅— 68 —H —H —H —H O

O C₂H₅— 70 —H —H —H —H O —CH₂CH₂— O nC₆H₁₃— 71 —H —H —H —H O —CH₂CH2CH₂—O CH₃O(CH₂)₃— 72 —H —H —H —H O —CH(CH═CH₂)CH₂— O CH₃— 73 —H —H —H —H O—CH₂CH₂— O NCCH₂CH₂CH(OMe)— 74 —H —H —H —H O —CH₂CH₂— O

75 —F —H —H —H O —CH₂CH₂— O nC₅H₁₁— 76 —Cl —H —H —H O —CH₂CH₂— O nC₅H₁₁—77 —F —H —H —H O —CH₂CH2CH₂— O C₂H₅— 78 —Cl —H —H —H O —CH₂CH2CH₂— OC₂H₅— 79 —F —H —H —H O —CH₂CH2CH₂— O iC₃H₇— 80 —Cl —H —H —H O—CH₂CH2CH₂— O iC₃H₇— 81 —H —H —H —H O

O CH₃— 82 —H —H —H —H O

O CH₃— 83 —H —H —H —H O

O CH₃— 84 —H —H —H —H O

O CH₃— 85 —H —H —H —H S

O C₂H₅— 87 —H —H —H —H S

O nC₃H₇— 88 —H —H —H —H O

O CH₃— 89 —H —H —H —H O —CH₂CH2CH₂— O nC₃H₇—

Compound Number W X Y Z —A—R¹—B—R² 90 —H —H —H —H2,6-dimethylmorpholinyl 91 —H —Cl —H —Cl morpholinyl 92 —H —Cl —H —Cl2,6-dimethylmorpholinyl 93 —H —H —H —H morpholinyl

The compounds of formula (1) thus produced are usually obtained as amixture of the E and Z forms, which can then be separated, via standardmeans known in the art, into each of those forms, if desired.

Fungicide Utility

The compounds of the present invention have been found to control fungi,particularly plant pathogens. When employed in the treatment of plantfungal diseases, the compounds are applied to the plants in a diseaseinhibiting and phytologically acceptable amount. Application may beperformed before and/or after the infection with fungi on plants.Application may also be made through treatment of seeds of plants, soilwhere plants grow, paddy fields for seedlings, or water for perfusion.

As used herein, the term “disease inhibiting and phytologicallyacceptable amount”, refers to an amount of a compound of the presentinvention which kills or inhibits the plant disease for which control isdesired, but is not significantly toxic to the plant. This amount willgenerally be from about 1 to 1000 ppm, with 10 to 500 ppm beingpreferred. The exact concentration of compound required varies with thefungal disease to be controlled, the type of formulation employed, themethod of application, the particular plant species, climate conditions,and the like. A suitable application rate is typically in the range fromabout 0.10 to about 4 pounds/Acre.

While the compounds of the present invention have significant activityfor agricultural use, such as, for example, for use with agriculturalcrops, many of the compounds are effective for use with horticulturalplants, stored grain and other non-plant loci, such as, for example,wood, paint, leather or carpet, to protect such materials from fungalinfestation.

The following experiments were performed in the laboratory to determinethe fungicidal efficacy of the compounds of the invention.

Compound Formulation: Compound formulation was accomplished bydissolving technical materials in acetone, with serial dilutions thenmade in acetone to obtain desired rates. Final treatment volumes wereobtained by adding nine volumes 0.05kOO aqueous Tween-20 or TritonX-100, depending upon the pathogen.

Downy Mildew of Grape (Plasmogara viticola-PLASVI) (96 Hour Protectant):Vines (cultivar Carignane) were grown from seed in a soilless peat-basedpotting mixture (Metromix) until the seedlings were 10-20 cm tall. Theseplants were then sprayed to run off with the test compound at a rate of100 ppm. After 96 hours the test plants were inoculated by spraying withan aqueous sporangia suspension of Plasmopara viticola. The plants werethen transferred to the greenhouse until disease developed on theuntreated control plants.

Powdery Mildew of Wheat (Erysiphe graminis-ERYSGT): Wheat (cultivarMonon) was grown in a soilless peat-based potting mixture (Metromix)until the seedlings were 1-2 leaf (BBCH 12). These plants were theninoculated with Erysiphe graminis by dusting spores from stock plantsonto the test plants. After 48 hours the plants were sprayed to run offwith the test compound at a rate of 25 ppm and then kept in thegreenhouse until disease developed on the untreated control plants.

Glume blotch of wheat (Leptosphaeria nodorum-LEPTNO): Wheat (cultivarMonon) was grown from seed in a soilless peat-based potting mixture(Metromix) until the seedlings were 1-2 leaf (BBCH 12). These plantswere then sprayed to run off with the test compound at a rate of 100ppm. After 24 hours the test plants were inoculated with an aqueousspore suspension of Leptosphaeria nodorum. The plants were thentransferred to the greenhouse until disease developed on the untreatedcontrol plants. Brown rust (Puccinia recondita-PUCCRT): Wheat (cultivarMonon) was grown from seed in a soilless peat-based potting mixture(Metromix) until the seedlings were 1-2 leaf (BBCH 12). These plantswere then sprayed to run off with the test compound at a rate of 100ppm. After 24 hours the test plants were inoculated with an aqueousspore suspension of Puccinia recondita. The plants were then transferredto the greenhouse until disease developed on the untreated controlplants.

Septoria leaf spot (Septoria tritici-SEPTTR): Wheat (cultivar Monon) wasgrown from seed in a soilless peat-based potting mixture (Metromix)until the seedlings were 1-2 leaf (BECH 12). These plants were thensprayed to run off with the test compound at a rate of 100 ppm. After 24hours the test plants were inoculated with an aqueous spore suspensionof Septoria tritici. The plants were then transferred to the greenhouseuntil disease developed on the untreated control plants.

The following table presents the activity of typical compounds of thepresent invention when evaluated in these experiments. The effectivenessof the test compounds in controlling disease was rated using thefollowing scale:

Compound Number PLASVI ERYSGT LEPTNO PUCCRT SEPTTR  1 ++ + ++ ++  2 ++ +++ ++  3 ++ +  4 − −  5 ++ −  6 ++  7 + ++  8 ++ −  9 ++ + 10 + ++ 11 ++12 − − 13 + − + 14 15 ++ ++ 16 ++ ++ + 17 ++ + ++ 18 ++ + ++ 19 + + ++20 + + + 21 ++ + 22 + ++ + 23 ++ ++ 24 ++ ++ + 25 ++ ++ 26 + ++ 27 + +28 ++ ++ 29 ++ + 30 ++ ++ 31 ++ ++ 32 ++ 33 ++ + 34 ++ ++ 35 ++ 36 ++ +37 ++ ++ 38 ++ 39 ++ 40 ++ + 41 ++ + 42 ++ ++ 43 ++ − 44 ++ ++ 45 ++ +46 ++ + 47 ++ ++ 48 + − 49 ++ ++ 50 ++ − 51 ++ ++ 52 ++ ++ + 53 ++ ++ −54 ++ ++ ++ 55 + + 56 ++ ++ 57 ++ ++ 58 ++ ++ 59 ++ 60 ++ ++ 61 ++ ++ 62++ + 63 ++ 64 ++ ++ 65 ++ ++ 66 ++ ++ 67 ++ 68 ++ + 69 ++ 70 + + 71 − 72− 73 − 74 ++ 75 ++ 76 ++ 77 ++ 78 ++ 79 ++ 80 ++ 81 + 82 ++ 83 ++ 84 ++85 − 86 ++ + 87 ++ 88 ++ + ++ + 89 − + − blank space = not tested − =0-24% control of plant disease + = 25-74% control of plant disease ++ =75-100 % control of plant disease

The compounds of this invention are preferably applied in the form of acomposition comprising one or more of the compounds of formula (1) witha phytologically-acceptable carrier. The compositions are eitherconcentrated formulations which are dispersed in water or another liquidfor application, or are dust or granular formulations which are appliedwithout further treatment. The compositions are prepared according toprocedures which are conventional in the agricultural chemical art, butwhich are novel and important because of the presence therein of thecompounds of this invention. Some description of the formulation of thecompositions is given to assure that agricultural chemists can readilyprepare desired compositions.

The dispersions in which the compounds are applied are most oftenaqueous suspensions or emulsions prepared from concentrated formulationsof the compounds. Such water-soluble, water suspendable, or emulsifiableformulations are either solids, usually known as wettable powders, orliquids, usually known as emulsifiable concentrates or aqueoussuspensions. The present invention contemplates all vehicles by whichthe compounds of this invention can be formulated for delivery for useas a fungicide. As will be readily appreciated, any material to whichthese compounds can be added may be used, provided they yield thedesired utility without significant interference with activity of thecompounds of this invention as antifungal agents.

Wettable powders, which may be compacted to form water dispersiblegranules, comprise an intimate mixture of the active compound, an inertcarrier and surfactants. The concentration of the active compound isusually from about 10% to about 90% w/w, more preferably about 25% toabout 75% w/w. In the preparation of wettable powder compositions, thetoxicant products can be compounded with any of the finely dividedsolids, such as prophyllite, talc, chalk, gypsum, Fuller's earth,bentonite, attapulgite, starch, casein, gluten, montmorillonite clays,diatomaceous earths, purified silicates or the like. In such operations,the finely divided carrier is ground or mixed with the toxicant in avolatile organic solvent. Effective surfactants, comprising from about0.5% to about 10% of the wettable powder, include sulfonated lignins,naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, andnon-ionic surfactants, such as ethylene oxide adducts of alkyl phenols.

Emulsifiable concentrates of the compounds of this invention comprise aconvenient concentration, such as from about 10% to about 50% w/w, in asuitable liquid. The compounds are dissolved in an inert carrier, whichis either a water miscible solvent or a mixture of water-immiscibleorganic solvents, and emulsifiers. The concentrates may be diluted withwater and oil to form spray mixtures in the form of oil-in-wateremulsions. Useful organic solvents include aromatics, especially thehigh-boiling naphthalenic and olefinic portions of petroleum such asheavy aromatic naphtha. Other organic solvents may also be used, suchas, for example, terpenic solvents, including rosin derivatives,aliphatic ketones, such as cyclohexanone, and complex alcohols, such as2-ethoxyethanol.

Emulsifiers which can be advantageously employed herein can be readilydetermined by those skilled in the art and include various nonionic,anionic, cationic and amphoteric emulsifiers, or a blend of two or moreemulsifiers. Examples of nonionic emulsifiers useful in preparing theemulsifiable concentrates include the polyalkylene glycol ethers andcondensation products of alkyl and aryl phenols, aliphatic alcohols,aliphatic amines or fatty acids with ethylene oxide, propylene oxidessuch as the ethoxylated alkyl phenols and carboxylic esters solubilizedwith the polyol or polyoxyalkylene. Cationic emulsifiers includequaternary ammonium compounds and fatty amine salts. Anionic emulsifiersinclude the oil-soluble salts (e.g., calcium) of alkylaryl sulphonicacids, oil soluble salts or sulphated polyglycol ethers and appropriatesalts of phosphated polyglycol ether.

Representative organic liquids which can be employed in preparing theemulsifiable concentrates of the present invention are the aromaticliquids such as xylene, propyl benzene fractions; or mixed naphthalenefractions, mineral oils, substituted aromatic organic liquids such asdioctyl phthalate; kerosene; dialkyl amides of various fatty acids,particularly the dimethyl amides of fatty glycols and glycol derivativessuch as the n-butyl ether, ethyl ether or methyl ether of diethyleneglycol, and the methyl ether of triethylene glycol. Mixtures of two ormore organic liquids are also often suitably employed in the preparationof the emulsifiable concentrate. The preferred organic liquids arexylene, and propyl benzene fractions, with xylene being most preferred.The surface active dispersing agents are usually employed in liquidcompositions and in the amount of from 0.1 to 20 percent by weight ofthe combined weight of the dispersing agent and active compound. Theactive compositions can also contain other compatible additives, forexample, plant growth regulators and other biologically active compoundsused in agriculture.

Aqueous suspensions comprise suspensions of water-insoluble compounds ofthis invention, dispersed in an aqueous vehicle at a concentration inthe range from about 5% to about 50% w/w. Suspensions are prepared byfinely grinding the compound, and vigorously mixing it into a vehiclecomprised of water and surfactants chosen from the same types abovediscussed. Inert ingredients, such as inorganic salts and synthetic ornatural gums, may also be added to increase the density and viscosity ofthe aqueous vehicle. It is often most effective to grind and mix thecompound at the same time by preparing the aqueous mixture andhomogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer.

The compounds may also be applied as granular compositions, which areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% w/w of the compound,dispersed in an inert carrier which consists entirely or in large partof coarsely divided attapulgite, bentonite, diatomite, clay or a similarinexpensive substance. Such compositions are usually prepared bydissolving the compound in a suitable solvent and applying it to agranular carrier which has been preformed to the appropriate particlesize, in the range of from about 0.5 to about 3 mm. Such compositionsmay also be formulated by making a dough or paste of the carrier andcompound, and crushing and drying to obtain the desired granularparticle.

Dusts containing the compounds are prepared simply by intimately mixingthe compound in powdered form with a suitable dusty agriculturalcarrier, such as, for example, kaolin clay, ground volcanic rock, andthe like. Dusts can suitably contain from about 1% to about 10% w/w ofthe compound.

The active compositions may contain adjuvant surfactants to enhancedeposition, wetting and penetration of the compositions onto the targetcrop and organism. These adjuvant surfactants may optionally be employedas a component of the formulation or as a tank mix. The amount ofadjuvant surfactant will vary from 0.01 percent to 1.0 percent v/v basedon a spray-volume of water, preferably 0.05 to 0.5%. Suitable adjuvantsurfactants include ethoxylated nonyl phenols, ethoxylated synthetic ornatural alcohols, salts of the esters or sulphosuccinic acids,ethoxylated organosilicones, ethoxylated fatty amines and blends ofsurfactants with mineral or vegetable oils.

The composition may optionally include fungicidal combinations whichcomprise at least li of one or more of the compounds of this inventionwith another pesticidal compound. Such additional pesticidal compoundsmay be fungicides, insecticides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present invention in the mediumselected for application, and not antagonistic to the activity of thepresent compounds. Accordingly, in such embodiments the other pesticidalcompound is employed as a supplemental toxicant for the same or for adifferent pesticidal use. The compounds in combination can generally bepresent in a ratio of from 1:100 to 100:1.

The present invention includes within its scope methods for the controlor prevention of fungal attack. These methods comprise applying to thelocus of the fungus, or to a locus in which the infestation is to beprevented (for example applying to cereal or grape plants), a fungicidalamount of one or more of the compounds of this invention orcompositions. The compounds are suitable for treatment of various plantsat fungicidal levels, while exhibiting low phytotoxicity. The compoundsare useful in a protectant or eradicant fashion. The compounds of thisinvention are applied by any of a variety of known techniques, either asthe compounds or as compositions including the compounds. For example,the compounds may be applied to the roots, seeds or foliage of plantsfor the control of various fungi, without damaging the commercial valueof the plants. The materials are applied in the form of any of thegenerally used formulation types, for example, as solutions, dusts,wettable powders, flowable concentrates, or emulsifiable concentrates.These materials are conveniently applied in various known fashions.

The compounds of this invention have been found to have significantfungicidal effect particularly for agricultural use. Many of thecompounds are particularly effective for use with agricultural crops andhorticultural plants, or with wood, paint, leather or carpet backing.

In particular, the compounds effectively control a variety ofundesirable fungi which infect useful plant crops. Activity has beendemonstrated for a variety of fungi, including for example the followingrepresentative fungi species: Downy Mildew of Grape (Plasmoparaviticola-PLASVI), Late Blight of Tomato (Phytophthora infestans -PHYTIN), Apple Scab (Venturia inaequalis-VENTIN), Brown Rust of Wheat(Puccinia recondita-PUCCRT), Stripe Rust of Wheat (Pucciniastriiformis-PUCCST), Rice Blast (Pyricularia oryzae-PYRIOR), CercosporaLeaf Spot of Beet (Cercospora beticola-CERCBE), Powdery Mildew of Wheat(Erysiphe graminis-ERYSGT), Leaf Blotch of Wheat (Septoriatritici-SEPTTR), Sheath Blight of Rice (Rhizoctonia solani-RHIZSO),Eyespot of Wheat (Pseudocercosporella herpotrichoides-PSDCHE), Brown Rotof Peach (Monilinia fructicola-MONIFC), Glume Blotch of Wheat (Septorianodorum-LEPTNO). It will be understood by those in the art that theefficacy of the compounds of this invention for the foregoing fungiestablishes the general utility of the compounds as fungicides.

The compounds of this invention have broad ranges of efficacy asfungicides. The exact amount of the active material to be applied isdependent not only on the specific active material being applied, butalso on the particular action desired, the fungal species to becontrolled, and the stage of growth thereof, as well as the part of theplant or other product to be contacted with the toxic active ingredient.Thus, all the active ingredients of the compounds of this invention, andcompositions containing the same, may not be equally effective atsimilar concentrations or against the same fungal species. The compoundsof this invention and compositions are effective in use with plants in adisease inhibiting and phytologically acceptable amount. The term“disease inhibiting and phytologically acceptable amount” refers to anamount of a compound which kills or inhibits the plant disease for whichcontrol is desired, but is not significantly toxic to the plant. Thisamount will generally be from about 1 to about 1000 ppm, with 10 to 500ppm being preferred. The exact concentration of compound required varieswith the fungal disease to be controlled, the type of formulationemployed, the method of application, the particular plant species,climate conditions, and the like. A suitable application rate istypically in the range from about 0.10 to about 4 pounds/acre.

What is claimed is:
 1. A compound of Formula (1)

wherein m is an integer 0-3; L is —CH₂O— or —CH₂—S—; X, Y, and Z areeach independently H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkyl,halo-C₁₋₆ alkoxy, halo, nitro, carbo-C₁₋₆ alkoxy, cyano, C₁₋₆ alkylthio,or halo-C₁₋₆ alkylthio; W is H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,halo-C₁₋₄ alkyl, or C₁₋₄ alkylthio; A is O, S, NR³, OCH₂, SCH₂; B is Oor S; R¹ is a C₁-C₄ alkyl group (optionally substituted by alkenyl,cycloalkyl, alkoxy, alkoxycarbonyl, aralkyl, cyano, cyanoalkyl, halo, orhaloalkyl), optionally substituted aryl or heteroaryl ring; R² is aC₁-C₈ alkyl (optionally substituted by alkenyl, cycloalkyl, alkoxy,alkoxycarbonyl, aralkyl, cyano, cyanoalkyl, halo, or haloalkyl), anoptionally substituted aryl or heteroaryl ring; and R³ is H or C₁₋₆alkyl.
 2. A compound of claim 1 of the formula

wherein the substituents are as defined in claim
 1. 3. A compound ofclaim 2 of the formula

wherein the substituents are as defined in claim
 1. 4. A compound ofclaim 3 of the formula

wherein the substituents are as defined claim in
 1. 5. A compound ofclaim 4 of the formula

wherein the substituents are as defined in claim
 1. 6. A compound ofclaim 5 wherein R¹—B—R² is —CH₂CH₂—O—nC₃H₇.
 7. A compound of claim 5wherein R¹—B—R² is


8. A fungicidal composition comprising the compound of claim 1 and aphytologically acceptable carrier.
 9. A fungicidal method whichcomprises applying to the locus to be treated a fungicidally-effectiveamount of a compound of formula (1)

wherein m is an integer 0-3; L is —CH₂O— or —CH₂S—; X, Y, and Z are eachindependently H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkyl, halo-C₁₋₆alkoxy, halo, nitro, carbo-C₁₋₆ alkoxy, cyano, C₁₋₆ alkylthio, orhalo-C₁₋₆ alkylthio; W is H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, halo-C₁₋₄alkyl, or C₁₋₄ alkylthio; A is O, S, NR³, OCH₂, SCH₂; B is O or S; R¹ isa C₁-C₄ alkyl group (optionally substituted by alkenyl, cycloalkyl,alkoxy, alkoxycarbonyl, aralkyl, cyano, cyanoalkyl, halo, or haloalkyl),optionally substituted aryl or heteroaryl ring; R² is a C₁-C₈ alkyl(optionally substituted by alkenyl, cycloalkyl, alkoxy, alkoxycarbonyl,aralkyl, cyano, cyanoalkyl, halo, or haloalkyl), an optionallysubstituted aryl or heteroaryl ring; and R³ is H or C₁₋₆ alkyl.
 10. Acompound of Formula (1)

wherein m is an integer 0-3; L is —CH₂O— or —CH₂S—; X, Y, and Z are eachindependently H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkyl, halo-C₁₋₆alkoxy, halo, nitro, carbo-C₁₋₆ alkoxy, cyano, C₁₋₆ alkylthio, orhalo-C₁₋₆ alkylthio; W is H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, halo-C₁₋₄alkyl, or C₁₋₄ alkylthio; A is O, S, NR³, OCH₂, SCH₂; —R¹—B—R² is2,2-dimethyl-1,3-dioxolan-4-yl; and R³ is H or C₁₋₆ alkyl.
 11. Afungicidal composition comprising the compound of claim 10 and aphytologically acceptable carrier.
 12. A fungicidal method whichcomprises applying to the locus to be treated a fungicidally-effectiveamount of a compound of formula (1)

wherein m is an integer 0-3; L is —CH₂O— or —CH₂S—; X, Y, and Z are eachindependently H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkyl, halo-C₁₋₆alkoxy, halo, nitro, carbo-C₁₋₆ alkoxy, cyano, C₁₋₆ alkylthio, orhalo-C₁₋₄ ₆ alkylthio; W is H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,halo-C₁₋₄ alkyl, or Ch₁₋₄ alkylthio; A is O, S, NR³, OCH₂, SCH₂;—R³—B—R² is 2,2-dimethyl-1,3-dioxolan-4-yl; and R³ is H or C₁₋₆ alkyl.